Zádori Dénes, Veres Gábor, Szalárdy Levente, Klivényi Péter, Toldi József, Vécsei László
Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Szeged, Hungary.
Department of Physiology, Anatomy and Neuroscience, Faculty of Science and Informatics, University of Szeged, Szeged, Hungary MTA-SZTE Neuroscience Research Group, Szeged, Hungary.
J Alzheimers Dis. 2014;42 Suppl 3:S177-87. doi: 10.3233/JAD-132621.
The impairment of glutamatergic neurotransmission plays an important role in the development of Alzheimer's disease (AD). The pathological process, which involves the production of amyloid-β peptides and hyperphosphorylated tau proteins, spreads over well-delineated neuroanatomical circuits. The gradual deterioration of proper synaptic functioning (via GluN2A-containing N-methyl-D-aspartate receptors, NMDARs) and the development of excitotoxicity (via GluN2B-containing NMDARs) in these structures both accompany the disease pathogenesis. Although one of the most important therapeutic targets would be glutamate excitotoxicity, the application of conventional anti-glutamatergic agents could result in further deterioration of synaptic transmission and intolerable side-effects. With regard to NMDAR antagonists with tolerable side-effects, ion channel blockers with low affinity, glycine site agents, and specific antagonists of polyamine site and GluN2B subunit may come into play. However, in the mirror of experimental data, only the application of ion channel blockers with pronounced voltage dependency, low affinity, and rapid unblocking kinetics (e.g., memantine) and specific antagonists of the GluN2B subunit (e.g., ifenprodil and certain kynurenic acid amides) resulted in desirable symptom amelioration. Therefore we propose that these kinds of chemical agents may have therapeutic potential for present and future drug development.
谷氨酸能神经传递受损在阿尔茨海默病（AD）的发展中起重要作用。这一病理过程涉及淀粉样β肽和过度磷酸化tau蛋白的产生，其在明确的神经解剖回路中扩散。这些结构中正常突触功能（通过含GluN2A的N-甲基-D-天冬氨酸受体，NMDARs）的逐渐恶化以及兴奋性毒性（通过含GluN2B的NMDARs）的发展均伴随疾病发病机制。尽管最重要的治疗靶点之一可能是谷氨酸兴奋性毒性，但应用传统的抗谷氨酸能药物可能导致突触传递进一步恶化和难以忍受的副作用。关于具有可耐受副作用的NMDAR拮抗剂，低亲和力离子通道阻滞剂、甘氨酸位点药物以及多胺位点和GluN2B亚基的特异性拮抗剂可能会发挥作用。然而，根据实验数据，只有应用具有明显电压依赖性、低亲和力和快速解阻动力学的离子通道阻滞剂（如美金刚）以及GluN2B亚基的特异性拮抗剂（如ifenprodil和某些犬尿氨酸酰胺）才能带来理想的症状改善。因此，我们认为这类化学药物可能对当前和未来的药物开发具有治疗潜力。
